Potential agents to target macrophages in CTD-ILD. The figure depicts potential strategies to target macrophages in the context of CTD-ILD according to the literature. (1) ABT-199 inhibits Bcl-2. As a result, ABT-199 augments caspase-3 activity and enhances macrophage apoptosis, counteracting lung fibrosis. (2) Anti-IL-33 blocks IL-33 action on ST2 and thereby downregulates IL-13 and TGF-β1 production, which decreases collagen synthesis by fibroblasts. (3) Clevudine, as an inhibitor of the PI3K/Akt signaling pathway, prevents M2 polarization and the subsequent fibrotic response of the lungs. (4) By inhibiting Cu,Zn-SOD-mediated H2O2 generation, leflunomide downregulates Jmjd3 expression, lowers M2 polarization, and diminishes lung fibrosis. (5) GW4869, which eliminates the secretion of AT1R-carrying exosomes from macrophages, decreases collagen synthesis in fibroblasts and ameliorates lung fibrosis. (6) IL-10 curbs TGF-β production in macrophages and prevents collagen deposition by fibroblasts. (7) Methyl palmitate blocks IκBα phosphorylation, reducing TNF-α and boosting IL-10 expression in macrophages, which inhibit lung inflammation and fibrosis. (8) After binding to GRP78, microcystin-LR interferes with UPR signaling, subsequently preventing M2 macrophage polarization and leading to attenuated lung fibrosis. (9) Niclosamide interferes with S100A4 production by macrophages, which ameliorates collagen production by fibroblasts. These changes culminate in reducing the fibrosis of the lungs. (10) Nintedanib limits M2 differentiation by blocking CSF1R and consequently improves fibrosis in a CTD-ILD model. (11) Pirfenidone acts on macrophages to block M2 polarization and, as a result, suppresses fibroblast proliferation and restricts lung fibrosis. (12) The β-catenin pathway inhibitor PRI-724, which blocks β-catenin signaling, lowers TGF-β production in macrophages and contributes to mitigated collagen production by fibroblasts. (13) rhPTX-2 prevents M2 differentiation and avoids PF deterioration. (14) Schisandra reduces TGF-β and downstream Smad3/Smad4 while stimulating Smad7 production. These signaling events disrupt M2 polarization and thereby improving lung fibrosis. (15) Ruxolitinib and (16) Tacrolimus, by inhibiting JAK/STAT signaling, suppress M2 polarizations and hence improve lung fibrosis in an animal model. Red arrow—increase; blue arrow—decrease; cross symbol—block; dashed line—act on
The Role of Macrophages in Connective Tissue Disease-Associated Interstitial Lung Disease: Focusing on Molecular Mechanisms and Potential Treatment Strategies (2023)
Chia-Chun Tseng, et al. Int J Mol Sci. 2023 Aug;24(15). Figure: F3.
